• Defects early in the pathway produce precursors which are neurotoxic and produce acute porphyrias. They show #autosomalDominant inheritance.
• More common are defects later on in the pathway cause accumulation of porphyrins leading to chronic porphyria; This is known as porphyria cutanea tarda.

[!TIP] Patient (esp. Female) with abdominal pain + neuropsychiatric features -> need to consider acute porphyria.

• Clinical features: Abdominal pain, neuropsychiatric features, seizures and fever.

• Can be precipitated by anaesthetic drugs and luteal phase of the menstrual cycle.

• Anaesthesia for suspected acute abdomen can be catastrophic.

• The defective enzyme in acute intermittent porphyria is porphobilinogen deaminase.

• The defect is in uroporphyrinogen decarboxylase.

• 80% of cases are acquired / sporadic; 20% are inherited.

• Uroporphyrinogen decarboxylase converts uroporphyrinogen III into coproporphyrinogen III.

• Presents with photosensitive blistering rash.

• Hypertrichosis and hyperpigmentation may be present.

• Liver disease is a common comorbidity:

  • Either caused by excessive hepatic porphyrins OR
  • liver disease due to hepatitic C / alcohol triggering porphyria.

• Triggers for attacks are caused by increased hepatic iron load but also alcohol, smoking, estrogens, hepatitis C or HIV.

• Phlebotomy - used to decrease the iron load.

• Hydroxycholorquine - increase the excretion of porphyrins.

• Cutaneous T cell lymphoma - usually limited to the skin. Looks like tinea versicolor.
• benign course

Sezary syndrome

• Sezary syndrome is an erythrodermic cutaneous T-cell lymphoma with the leukemic component.

    1. Overnight 1mg dexamethasone suppression test

• Primary adrenal insufficiency is also called Addison's disease
• Features: ⬇Na, ⬆K, ⬇pH
• Diagnosis
  • Screening: morning cortisol level.
  • confirmatory: Short synacthen test. (plasma cortisol is measure before and 30 minutes after administration of IM 250ug of Synacthen)
  • Other investigations (not related to Addison's disease):
    • 24 hour urinary free cortisol is used to check for cushing's syndrome; not Addison's.

• About 90% are subclinical infections.
• Most symptomatic patients have anicteric disease
• Conjunctival suffusion is an important sign - minority have a sub conjunctival haemorrhage; but suffusion is the commoner manifestation.
• Organism stains poorly with normal stain -> dark field microscopy / silver stain must be done.
• But DG microscopy has low sensitivity and specificity -> so not used as a confirmatory test.

• MAT is a method to detect antibodies in patient serum.
  • MAT is performed by incubating patient serum with various serovars of leptospires. MAT titer is obtained by testing various serum dilutions with the positive serovar. The serovar that reacts with patient serum is suggested to be the infecting serovar.
  • MAT is considered the gold standard. (but apparently less sensitive the IgM serology by ELISA)-
    • 4 fold rise in titer or titer > 1:320 is diangnostic.

• Pulsed steroid therapy can be given for severe disease (esp. pulmonary involvement)

Indications for ICU care (according to SL guidelines)

• Any haemodynamic instability
• Hypotension not responding to fluid, CRFT > 2 seconds.
• Impaired oxygenation (sat < 92%)
• RR > 30 / min
• Pulmonary haemorrhage / ARDS
• reduced GCS
• Organ dysfunction

Complications of leptospirosis

Renal

• First is a tubular nephritis -> Subsequently GFR drop.
• So usually, AKI is non oligaemic and hypokalemic; with more severe AKI, it become oliguric with hyperkalemia -> that has a poor prognosis.
  Pulmonary
• 5% develop pulmonary hemorrhage - they have 50 to 70% mortality.
• Risk factors : male, smoker, age > 40 years, high bilirubin, high creatinine and specific serovars of leptospirosis.
  Hepatic complications
• Mild to moderate elevation of tranaminase levels.
• There is a cholestatic picture.
• Massive hepatic necrosis is rare.
  Haematologic complications:
• Thrombocytopenia
• DIC, HUS, TTP.
• bleeding with platelet < 50k is an indication for platelet transfusion.

Psoriatic arthritis is associated with HLA-B27.

Imaging

Psoriatic arthritis Vs. Rheumatoid arthritis

Differentiation is clinically important because prognosis and management are different.

Summary of enzymes involved

HMG-CoA reductase: Rate limiting enzyme in cholesterol sythesis : found in the liver and ? other tissues
LCAT : the enzyme synthesized by the liver and attached to HDL which exterifies cholesterol so that it becomes trapped inside HDL. Required for reverse transport of cholesterol.
LPL: lipoprotein lipase: the enzyme found on tissues which removes lipids from VLDL and it's derivatives, increasing their density.
If there is acidosis (pH < 7.2 or HCO3 < 15) or high ketonemia, manage as DKA.
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Loss of this function leads to leads to chronic complement mediated haemolysis, more pronounced at night during hypoxia. (Dark urine in the morning)

• Lack of CD59 on platelets predisposes to thrombosis.
  • Old test: Ham's test : Checks for acid induced haemolysis. (Patient RBCs put into acidified serum) -> haemolysis occurs in PNH (but it's a non specific test). (Mnaenomic: Hams - h for pH).

+ it is **non pruritic**, starts on the abdomen and **spreads *outwards***. (Spares palms and soles) 

Trombiculid mite = 'harvest' mite

Endemic typhus serves as the prototype for pathogenesis:
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[!INFO] DCT physiology

• Reabsorbs 5% of the filtered potassium.
• Contains thiazide sensitive Na/Cl co-transporter.
• Also contains TRPV-5 for calcium reabsorption.

Inheritance: #autosomal-Recessive

• Thiazides and Gitelman affect the same transporter (NCCT)

These changes (except the lack of hyponatremia) are very similar to changes caused by chronic thiazide use.
2. It causes recurring episodes of microscopic or gross haematuria lasting a few days. Usually recurs every few months after the onset. Can present as microscopic haematuria as well.
1. in PSGN, the haematuria develops 1-2 weeks after the respiratory infection.
4. Begins with haematuria 1-2 days after non specific upper respiratory tract infection. (said to be conincidental with the infection)
5. Pathogenesis may be due to dysregulated mucosal type IgA responsones (see K and C page 1362)
6. Hallmark is IgA deposition in the mesangium. (Mesangial deposist are granular deposits)
7. May be related to Henoch Schonlein purpura which has mesangial IgA deposition as well as systemic involvement.
3. Proteinuria > 1g day (if so, 25% progress to ESKD)
6. Apparently presence of macroscopic haematuria is a good prognostic factor because patients present earlier.

Symptoms Usually more prominent on one side at first but then become bilateral.

• Parkinsonian tremmor is usually unilateral at first. Doesn't cause much disability (as it reduced with actions).
• Tremor starts in the hands. (increases with emotion and stress); reduce with action. (It is a rest tremor) (examined with hands placed on the lap and distracting the patient)

Other motor symptoms:

• Postural - stooped posture with shuffling gain.
  • Increased risk of falls with postural instability; it is a feature of late stage disease.
  • Pull test is done ->
• Gait - reduced arm swinging., predominantly on one side, short step length. (+ many other signs to ellicit)
• mask like face
• Reduced spontaneous blinking -> serpentine stare.

  - Domperidone **does not cross the blood brain barrier**

8. Endocrine: reduced testosterone (due to Leydig cell dysfunction) [Source](https://emedicine.medscape.com/article/120858-overview)

• Activated charcoal isn't effective
• Long term, may need liver transplantation.
• Antidotes: Ethanol and fomepizole.
  | Dermatologic condition | Associated |
  | ---- | ---- |
  | Hyperkeratotic and proliferative dermatoses | - |
  | [[2022 General Medicine Paper-May#Acanthosis nigricans]] | |
  | Florid cutaneous papillomatosis (rapid eruption of warts) | Stomach cancer |
  | Sign of Leser-Trelat (rapid appearance of seborrheic keratoses) | Gastrointestinal adenocarcinoma AND many others |
  | Tripe palm (velvety thickening of palmar skin) | Gastric or lung cancer |
  | Icthyosis | Hodgkin's lymphoma |
  | Palmoplantar keratoderma | Associated with SQC of oesophagus = Howel-Evans Xn |
  | Bazex Xn: psoriatic like plaques on fingers and toes (acrokeratosis paraneoplastica | SQC of aerodigestive tract |
  | Inflammatory dermatoses - erythematous or violaceous skin eruptions | |
  | Sweet syndnrome (dermal,non vasculitic neutrophil infiltration with fever + neutrophilia) | Acute myeloid leukemia, lymphoma |
  | Dermatomyositis | Ovarian, breast, cervical,uterine + others |
  | Erythroderma (usually caused by psoriasis or atopic dermatitis) | Cutaneous T cell lymphoma |
  | Erythroderma gyratum repens | Bronchogenic carcinoma |
  | Pancreatic panniculitis | Pancreatic cancer |
  | paraneoplastic pemphigus (PAMS) | Non-hodgkin lymphoma, CLL |
  | Mucous Membrane pemphigoid | Unspecified but associated with malignancy |
  | - | |
  | Hyperpigmentation | |
  | Hyperpigmentation in ectopic ACTH poduction (ectopic cushing's syndrome) | Small cell lung CA |
  | ( POMC produced by the tumour is a precursor of ACTH and MSH ) | |
  | Generalized dermal melanosis | Extensive metastatic melanoma |
  | Skin manifestations of amyloidosis [[2022-November#Amyloidosis]] | plasma cell dyscrasias such as multiple myeloma, and less frequently, Waldenström macroglobulinemia |

• reduce alcohol - specially beer, avoid high fructose foods (like soft drinks)
• Reduce total calorie and cholesterol intake.
• Avoid red meat, spinach.
• First few episodes of gout are managed symptomatically as above. (new guidelines recommend ULT from first episode)

• [[Hormone Physiology#Adrenaline synthesis]]

Interface hepatitis is seen, just like autoimmune hepatitis.
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🔖Extrahepatic manifestations of hepatitis B

• Serum sickness like syndrome
• Oral lichen planus
• Papular acrodermatitis
• 
  • Which is also called ?Gianotti Crosti syndrome
    ++ /dev/null

• and lincosamide - clindamycin.

Symptoms : N/V, headache,
motor effects: nystagmus, tremor, cerebellar ataxia.

Phenytoin side effects

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• TCAs have been overall surpassed by SSRIs probably because of their toxicity
• Mechanism : Inhibition of presynaptic neurotransmitter reuptake
• Toxic effects:
  • Cardiac conduction abnormalities ( conduction defects due to increased refractory period, prolonged repolarization) occur during tricyclic antidepressant (TCA) poisoning because TCAs inhibit the fast sodium channels in the His-Purkinje system and myocardium -> slowing down of conduction; Most suggestive feature: widened QRS, prolongation of PR and QT also possible)
  • Metabolic acidosis occurs in severe poisoning. Acidosis augments drug toxicity.
  • 
• Hypotension From peripheral alpha 1 blockade as well as cardiac effects
• Antimuscarinic effects - tachycardia, hyperthermia, flushing, dilated pupils
• CNS effects: sedation, but may also include confusion, delirium, or hallucinations
• increases pH (goal 7.5) - favors unionised form of the drug -> less affinity to bind to sodium channels.
• Benzodiazepines for agitation
• Saline for hypotension
• Despite prominent anticholinergic toxicity in some, physostigmine is contraindicated (incr. risk of arrest)

Antipsychotic drugs

Causes of hyperprolactinaemia

#2023GM-NOV/Q30
Pathological causes

• Lactotroph adenoma
• Decreased dopaminergic inhibition
• Other hypothalaic or pituitary disorders

Drugs:

• Antipsychotics : commonest drugs causing hyperprolactinaemia (eg. Haloperidol, risperidone)
  • Newer drugs: occurs with amisulpride.
  • Does not occur with clozapine.
• SSRI's do NOT cause hyperprolactinaemia.
• Other drugs:
  • Metoclopramide (centrally acting dopamine and serotonin angatonist) and domperidone (peripherally acting dopamine antagonist) can cause hyperprolactinaemia .
    • Domperidone does not cross the blood brain barrier.
    • Methyldopa inhibits dopamine synthesis.